Biomarkers and Pathogenesis of MS: From Mouse to Human

MS 的生物标志物和发病机制：从小鼠到人类

基本信息

批准号：
9085399
负责人：
DOROTHY ANNE CROSS
金额：
$ 123.62万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-25 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9085399
关键词：
Address Affect Animal Model Autoimmune Diseases Biological Markers Biopsy Blood - brain barrier anatomy Brain CNS autoimmunity Cells Chronic Disease Clinical Communication Demyelinations Development Diffusion Disease Drops Functional disorder Goals Histology Human Image Immune Inflammation Inflammatory Invaded Lead Lesion Leukocytes Life Link Magnetic Resonance Imaging Measures Methods Multiple Sclerosis Mus Myelin Optic Nerve Pathogenesis Pathology Persons Program Research Project Grants Progressive Disease Research Research Design Research Personnel Sampling Studies Signal Transduction Spinal Cord Staging Testing Time Tissue Banking Tissue Banks Tissue Sample Vascular Permeabilities axon injury base design human disease human tissue imaging biomarker imaging modality improved innovation intravital microscopy leukocyte activation mouse model multiple sclerosis patient neuroimaging neuroimmunology non-invasive imaging novel novel therapeutic intervention novel therapeutics programs public health relevance repaired spectrograph white matter injury

项目摘要

DESCRIPTION (provided by applicant): This is a revised renewal application for a highly productive Program Project, "Biomarkers and Pathogenesis of MS: From Mouse to Human," comprised of three projects, a Statistical Core, an Animal Model/Human Tissue Bank Core and an Imaging Core that are focused on understanding mechanisms of pathogenesis of CNS inflammatory autoimmune disorders, especially multiple sclerosis (MS). Better understanding of the mechanisms of MS progression, and what underlies the continued axonal damage and drop-out would help guide development of new therapeutics for this common disease. Additionally, an urgent need exists for innovative methods to measure CNS inflammation, demyelination and axonal injury, as well as CNS repair, not only to better understand human MS pathogenesis, but also to expedite testing of novel therapeutics. A major innovation was achieved during our first five years with our development of the novel Diffusion Basis Spectrum Imaging (DBSI) which we now propose to definitively validate and carry forward to address current needs. Following encouragement and guidance from initial reviewers, we expanded our prior focus to encompass mechanistic studies of the communication between the invading inflammatory cells and resident cells in the CNS, leading to loss of blood-brain barrier integrity. State-of-the-art imaging modalities will be used. The three P01 projects are linked thematically with the goals of defining the interface between blood-brain barrier signaling and immune cell entry and how this impacts the development of persistent inflammatory lesions, and axonal pathologies. The latter, in particular, may underlie progressive MS. Each project uses all three Cores that provide statistical, animal model/human tissue bank, imaging and administrative support. Overall objectives are to (1) develop and test novel cutting edge noninvasive and specific MRI biomarkers of white matter injuries using animal models, human tissues, and MS patients; and (2) to address and target the mechanisms by which changes in vascular permeability impact leukocyte activation and entry into CNS.

描述（由申请人提供）：这是一项高效计划项目“MS 的生物标志物和发病机制：从小鼠到人类”的修订续展申请，由三个项目组成：统计核心、动物模型/人体组织库核心和成像核心，专注于了解中枢神经系统炎症性自身免疫性疾病，特别是多发性硬化症（MS）的发病机制。更好地了解多发性硬化症进展的机制以及持续轴突损伤和脱落的原因将有助于指导针对这种常见疾病的新疗法的开发。此外，迫切需要测量中枢神经系统炎症、脱髓鞘和轴突损伤以及中枢神经系统修复的创新方法，不仅可以更好地了解人类多发性硬化症的发病机制，还可以加快新疗法的测试。我们在前五年中实现了一项重大创新，开发了新型扩散基础光谱成像 (DBSI)，我们现在建议对其进行明确验证并继续发展以满足当前需求。在最初审稿人的鼓励和指导下，我们将先前的重点扩大到对中枢神经系统中入侵的炎症细胞和驻留细胞之间的通讯进行机制研究，从而导致血脑屏障完整性丧失。将使用最先进的成像方式。这三个 P01 项目在主题上与定义血脑屏障信号传导和免疫细胞进入之间的界面以及这如何影响持续性炎症病变和轴突病理的发展的目标相关。尤其是后者可能是进行性多发性硬化症的基础。每个项目都使用提供统计、动物模型/人体组织库、成像和管理支持的所有三个核心。总体目标是 (1) 使用动物模型、人体组织和多发性硬化症患者开发和测试白质损伤的新型尖端无创和特异性 MRI 生物标志物； (2) 解决和瞄准血管通透性变化影响白细胞激活和进入中枢神经系统的机制。